Schizophrenia is a neurodevelopmental syndrome that affects approximately 1 percent of the U.S. population and is characterized by the presence of hallucinations and delusions. Genetic factors are thought to account for the majority of the vulnerability to illness for this syndrome. These genetic factors are thought to be composed of major, moderate ant mild effect loci. The identification and characterization of genetic factors of even mild effect loci is a critical step in the process of understanding the pathogenesis of this group of disorders. In prior moleular studies, the candidate has identified an exonic polymorphism (HOPA12bP) in a critical portion of a gene for a thyroid receptor co-activator named HOPAthat is associated with a behavioral endophenotype that include schizophrenia and hypothyroidism. In this five year training grant, the candidate proposes to focus on the behavioral syndrome that is associated with the polymorphism and 1) demonstrate segregation of the polymorphism with illness. 2 refine the phenotype associated with the polymorphism, and 3) identify other mutations that may be related to illness. Scientific Aims of this grant are 1). Peform case control analyses on schizophrenic probands with the HOPA12bp polymorphism. Schizophrenic HOPA probands will be identified and compared to matched case controls for cognitive/behavioral, endocrinological and medical differences. 2. Conduct a focused linkage study of the families of HOPA12bp probands. Structured interviews will be used to assess the presence of cognitive/behavioral and medical co-morbidity in the first-degree relatives of control and HOPA12bP probands. These results will be correlated with genetic status. 3). Conduct SSCP analysis across the HOPA Gene to detect other potentially pathogenic mutations. Mutation analysis will be performed using DNA from other schizophrenic patients to detect other mutations in theHOPA gene that can result in result in this syndrome or related phenotypes. Training Aims of this grant are to 1) develop clinical skills in the diagnosis and standardized measurement of complex behavior and endocrinological disorders, and 2) learn medical and psychiatric epidemiology, ethics, and biostatistical approaches to complex disorders. The net effect will be to produce an independent investigator capable of functional and translational research.